I study pharmaceutical innovation, what causes it and how to get more of it. Several of my papers, published in Nature and Science, have helped stimulate a rethinking of the industry business model. In 2012, the popular newsletter FiercePharma named me one of the 25 most influential people in biopharma. In 2013, I became a Senior Fellow at FasterCures (a center of the Milken Institute). Besides doing research, I spend a lot of time helping organizations – big, small, public, private, US and non-US – become better innovators. I learned my trade in the 30 years I spent in the industry at Eli Lilly. Before that, I trained as an animal scientist in France and earned additional degrees in business and economics from Stanford and UC-Davis. I serve on various boards and advisory bodies, including at NCATS, the Institute of Medicine, Glenmark Pharmaceuticals, think tanks and foundations.

23andMe: A Fumbling Gene In Its Corporate DNA?

Last year, I gave my family what I thought would be a special Christmas treat. I bought 5 test kits from 23andMe — on sale at $99 each — and stuffed them in the family’s stockings. As one might expect, I got quizzical looks as they unpacked their test tubes, but we all spat in good humor and sent them away, encouraged by the inner belief that it was all part of a great scientific experiment.

It was my turn to be astonished when the results came back. My daughter, as expected, got half of her genes from my wife and half from myself. My son, however, got half of his from my wife, but only 47.5% from me. Now, he is a crafty guy, but how did he pull that off? And who is the interloper? I jokingly asked my wife for insights about this, but she disclaimed any involvement. For a while I thought that 23andMe’s Quality Control would surely discover the problem and contact my son, but that call never came. Two and a half percent is a serious error, but perhaps it was just a freak result and not the true error rate. Now I am not so sure.

But that’s not all. As I read through my report, discovering clues to my ancestry and learning about scary diseases for which I thankfully have no genetic predisposition, a few things caught my attention. For instance, I learned that I do not produce lactase, an enzyme involved in the digestion of dairy products, and am therefore likely to be lactose intolerant. But I am also a cheese lover, and we seldom finish a meal at home without partaking of a full cheese tray. And as far as I remember, I have never suffered the slightest inconvenience. I also learned that I face both slightly higher odds of Celiac disease, and lower odds of developing it depending upon whose research I choose to believe. Makes no sense? Read on.

My wife and I love coffee, and have drunk it in roughly equal, but sizeable quantities for many years. Last year though, she stopped drinking it at night because she felt that it interfered with her sleep. So I now enjoy it alone, as she looks on with envy while I sip my usual brew after dinner. Yet according to our genes, she metabolizes caffeine quickly, and I do it slowly. So she should be the one enjoying it while I should be the one looking on, but that’s not the way it is. And by the way, I may be a slow metabolizer, but will be fast asleep within an hour of finishing my cup, if I lay down.

This is not to say that genotyping is useless. It simply means that, under our current knowledge, there is often a tenuous relationship, at best, between selected genes and phenotypes. I do not doubt that I have the mutations that make me lactase-deficient and a slow metabolizer of caffeine, but, in my case, they are irrelevant. Their effects are mitigated by things we do not know or understand, such as other genes or perhaps the microbiome. The point is that if I cannot trust 23andMe to tell me much of value about my risk factor for Celiac, or my ability to digest dairy products or coffee, or to get my son’s results right, can I trust it for anything? What should I do if it tells me that I am at higher risk of developing Alzheimer’s or lung cancer? The answer is… not lose any sleep about it.

As one might expect, 23andMe’s results about health risks are carefully worded, stressing that they are based on few reports about specific populations of certain ages. And that is the problem. Extrapolating from such small groups to all comers is often inappropriate. A risk is unknown if it cannot be described statistically. For many diseases, we can hardly describe the population risk adequately, and extrapolating the little we know to the individual is unreliable. I may have a 0.49% chance of developing chronic kidney disease, but what is the accuracy of that estimate, and how much of it is driven by genetics vs. lifestyle or the environment? In some cases, such as rare diseases caused by single faulty genes, having a certain mutation guarantees that a disease will develop. But numerous diseases are caused by multiple mutations, many of which are unknown or too poorly understood to make meaningful inferences. Under our current state of knowledge, it would be more helpful to tell someone “you have the mutation XYZ and it does not mean a thing. However, if you are worried about it, this is what you can do to lower your unknown odds of developing disease ABC: do not smoke, keep your blood pressure under control” or whatever may be appropriate.

This being said, the business of 23andMe and the research that it enables deserve to be pursued. Traditional clinical research faces severe limitations and is ill-suited to help us understand the relationship between genotype and phenotype. We have 24,000 genes which can malfunction alone or in common, but only a few hundred phenotypes for major diseases. Many flawed genes can produce the same phenotype, and disentangling what causes what is a challenge of staggering complexity. It takes years and millions of dollars to complete one trial that may “validate” a biomarker, and such validation is often little more than a signal that a gene may play a role in the etiology of a disease. If medicine is to progress at a pace consistent with society’s expectations — and its resources — we must harness more effective tools such as those that help us understand how genetic variations impact an entire population instead of small samples controlled for factors that may not even be relevant.

It is clear that 23andMe suffers from serious management weaknesses that it must fix. Quality control is an issue, and the way it communicates information about health risks and traits must be reconsidered to better acknowledge the extent of our ignorance. FDA acted properly in view of 23andMe’s cavalier attitude toward its regulatory obligations and its failure to meet past commitments. However, it would be a setback for science if 23andMe were not allowed to proceed. For its research model to deliver, it needs more people, far more people in its database. A campaign to sign up a million customers is a good start, and not losing momentum is essential. Perhaps 23andMe and FDA can find an accommodation — such as a consent order — that allows 23andMe to move forward while catching up on its overdue obligations, under threat of financial penalties or even perhaps the licensing of its database.

This spat is bigger than 23andMe. It’s about another way to do science that can greatly enrich the current dominant approach that is based on the 65-year old randomized-controlled trial concept. We all stand to gain if 23andMe — or its eventual licensee — succeeds. Let’s give it a chance, but be clear about the consequences.

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There are even more serious topics that should stimulate a general public discussion and instant actions from all players in this field! Bernard’s experience is in line with Lukas. He got hit much harder; i.e. he was diagnosted fatally ill and only by digging deep into genomics and analysing the raw data including 23andMe’s algorithm he “cured” himself! http://qz.com/151311/why-23andme-might-have-the-fda-worried-it-gave-me-a-false-result/#!

However, the recent discussion on 23andMe’s business model merits further thoughts; see also “23andMe Is Terrifying, But Not for the Reasons the FDA Thinks” http://www.scientificamerican.com/article.cfm?id=23andme-is-terrifying-but-not-for-reasons-fda#! What have we learend from the NSA affair and other intrusions into “safe” databases? Databases can be hacked, data are being stolen for greed. I am most concerned about the pace how most sensitive personal data are being collected also by non-profit initiatives, while safety & security issues are definitely not being solved. Who does not believe that the immense value of these kind of well documented and curated personal data will not attract substantial criminal energy? I am a fierce believer in Big DATA which will eventually enable Precision Medicine and obviously new, disruptive business. But if we do not take the right steps we may loose our clients/customers and patients trust and this would be extremely damaging to all efforts to collect data. Not least for this reason Eric Schmidt was furiously commenting on the NSA. Just imagine what would happen if even more senstive data would be stolen and/or abused!

Your wife will share more DNA with your son than you do, as he and your wife share an X chromosome (while you an your son share an Y chromosome that is a lot smaller). Both you and your wife gave an X chromosome to your daughter, so you should expect this to be closer to 50/50. So this does not indicate a problem with 23&Me (unless they explicitly say that this is for the autosomes only, i.e. excluding X & Y). It is perhaps the case that this feature needs more explanation, to avoid frustration/confusion along these lines.

More generally I think 23&me does a reasonably good job of describing the uncertainty in its predictions. For example, the traits you quote in general have presentations that describe some of the complications. Part of the problem is that most people do not have a good intuition for probabilistic statements and genetics (including genetic counselors). This means that human geneticists and 23&me, or companies like it, will have to do a lot of ground work to educate people to understand genetic risks. How this can be done in a responsible way, that avoids causing confusion/distress is a big question, but one that we will have to face as a society.

Granted, but the percentages of DNA contributed by my wife and I should still add up to 100%, and they do not. Somewhere there is a problem that surprisingly does not seem to bother 23andMe. Has the sample been contaminated? How often does it happen? Why was the problem not caught?

It also seems that 23andMe calculates individual risk by adjusting population risk for ethnicity and age, as if these were the only relevant factors. They are perhaps the easiest to correct for, but it is a very crude approach, and it does not say much about the uncertainty attached to the estimate.

I agree that there is a lot of education to do, and perhaps it should start by explaining to customers why their calculated risk factors are uncertain and subject to significant revisions.

No, they shouldn’t necessarily add up to 100% because on your son’s page they are not reporting the fraction of your son’s genome that was inherited from each of his parents, but rather the fraction of you and your wife’s genomes which match your son. There is a subtle difference.

Your son got 22 autosomes and an X chromosome from your wife, and 22 autosomes and a Y chromosome from you. Your wife herself has 44 autosomes (in 22 pairs) and 2 X chromosomes, while you have 44 autosomes, an X, and a Y (which is smaller than the X). When you go to your son’s page and check how much of your wife’s genome matches his, it is 50% because she passed on exactly 50% of her genome. You, however, passed on slightly less than 50% of your genome because you passed on your Y, which is shorter than your X, thus leading to the asymmetry. It’s just a consequence of the way inheritance works, and the fact that men have slightly less DNA than women.

If you go to your page, and check the fraction of your son’s genome that he shares with you, and then go to your wife’s page and check the fraction of his genome that he shares with her, those numbers should add up to 100%. They should be in the neighborhood of 50/(50+47.5) = 51.3 for your wife’s contribution and 47.5/(50+47.5) = 48.7 for yours.

It’s true that 23andme could probably do a better job of explaining why these things happen, but it’s not an error.

There are all kinds of cheese ranging from fresh to aged and hard, and everything in between. The lactose content varies with the type of processing. Fresh cheese products such as ricotta, cottage or feta cheese have a higher lactose content that almost matches that of unprocessed dairy products, i.e., up to 5%. (Velveeta — if you call it a cheese — actually has a lactose content that is over 9% or about double that of fresh milk). Soft unripened cheese (e.g., cream cheese or farmer cheese) has a lactose content of about 2.5% to 3.5%. Ripened, aged cheese have the lowest lactose content, but are generally not lactose-free. In fact the mere existence of some cheese being marketed as “lactose-free” suggests that most others are not.

For more details, I am happy to refer you to the following websites that will inform you about the lactose content of dairy products: